Drug Safety Information on "Fen-Phen" from Center for Drug Evaluation, FDA

1. What is "fen-phen"?

Fen-phen refers to the use in combination of fenfluramine and phentermine. Phentermine has also been used in combination with dexfenfluramine ("dexfen-phen"). Fenfluramine ("fen") and phentermine ("phen") are prescription medications that have been approved by the FDA for many years as appetite suppressants for the short-term (a few weeks) management of obesity. Phentermine was approved in 1959 and fenfluramine in 1973. Dexfenfluramine (Redux) was approved in 1996 for use as an appetite suppressant in the management of obesity. Recently, some physicians have prescribed fenfluramine or dexfenfluramine in combination with phentermine, often for extended periods of time, for use in weight loss programs. Use of drugs in ways other than described in the FDA-approved label is called "off-label use." In the case of fen-phen and dexfen-phen, no studies were presented to the FDA to demonstrate either the effectiveness or safety of the drugs taken in combination.

2. What is the difference between fenfluramine and dexfenfluramine?

Fenfluramine (Pondimin) contains dexfenfluramine and levofenfluramine. Levofenfluramine may have some activities not directly related to appetite suppression. Dexfenfluramine (Redux) contains only dexfenfluramine.

3. What is the new evidence that prompted withdrawal of fenfluramine and dexfenfluramine?

On July 8, 1997, the Mayo Clinic reported 24 patients developed heart valve disease after taking fen-phen. In five patients who underwent valve replacement surgery, the diseased valves were found to have distinctive features similar to those seen in carcinoid syndrome. The cluster of unusual cases of valve disease in fen-phen users suggested that there might be an association between fen-phen use and valve disease.

On July 8, FDA issued a Public Health Advisory that described the Mayo findings. The Mayo findings were reported in the August 28 issue of the New England Journal of Medicine, along with an FDA letter to the editor describing additional cases. FDA has received over 100 reports (including the original 24 Mayo cases) of heart valve disease associated mainly with fen-phen. There were also reports of cases of heart valve disease in patients taking only fenfluramine or dexfenfluramine. No cases meeting FDA's definition of a case were reported in patients taking phentermine alone.

Within the past several weeks, additional information received by the FDA has raised more concern. Most of the cases previously brought to the FDA's attention were in patients who had symptoms of heart disease. Recently, FDA has received reports from five physicians who had performed heart studies (echocardiograms) on patients who had received fen-phen or dexfen-phen and did not have symptoms of heart disease. Of 291 asymptomatic patients screened, about 30 percent had abnormal valve findings, primarily aortic regurgitation. Based on these data, the manufacturers have agreed to withdraw the products from the market and FDA has recommended that patients stop taking the drugs.

4. Why isn't phentermine being withdrawn from the market?

At the present time, no cases of heart valve disease meeting FDA's case definition have been reported with phentermine alone. Analysis of the data points to an association of heart valve disease with fenfluramine and dexfenfluramine.

5. Why wasn't this problem discovered earlier?

The type of valve disease that FDA believes may be associated with fenfluramine and dexfenfluramine is an extremely unusual type of drug reaction. Because valve disease is not usually associated with drug use, it is not normally screened for in human clinical testing of drugs. Since valvular heart disease is not screened for in clinical trials, it would usually not be detected unless patients developed symptoms. No cases were detected in 500 patients followed for one year in a clinical trial of dexfenfluramine. Furthermore, asymptomatic heart valve disease (heart valve disease without symptoms) would not likely be detected in patients taking the drugs as part of a weight loss program. The number of patients who have been reported to have symptoms of heart valve disease associated with recent exposure to the drugs has been very small, compared to the number of recent prescriptions, although there may be a delay in the development of symptoms. And even in symptomatic patients, the link between the symptoms and drug use may not be obvious because such a reaction is not common. These factors may explain why this problem was not discovered earlier.

During the last few years, there has been a marked increase in amount and duration of use of fenfluramine, as it became widely prescribed as part of the fen-phen regimen..

In 1992, articles were published about study results suggesting that the combined use of phentermine and fenfluramine would result in significant weight loss when used over an extended period of time. The results of these studies were not reviewed by FDA, and the conclusion about long-term use of the combination of drugs has not received FDA approval. The increased magnitude and duration of use probably led to an increase in the number of cases of symptomatic heart valve disease, which may have contributed to the recent recognition of this association.

With respect to dexfenfluramine (Redux), which was approved on April 29, 1996, the labeling states that safety has not been shown for longer than one year of use. This reflects the length of the study upon which dexfenfluramine was approved. It was a one-year European study of 1,000 subjects, half of whom were treated with dexfenfluramine. The study population was 80 percent women with an average age of 41. Heart disease was not noted in the study. A follow-up study directed toward uncovering heart disease after termination of the study was not performed because there was no reason to believe at that time that the heart was affected. In addition, dexfenfluramine had been marketed in Europe for over a decade without detection of an association between dexfenfluramine and heart valve problems. FDA is currently trying to obtain such follow-up.

6. What is valvular heart disease?

The heart contains four major valves that regulate the flow of blood through the heart and to the lungs and general circulation. Disease may cause excessive tightness (stenosis) or leakiness (regurgitation) of the valves. In the case of valve disease associated with fenfluramine and dexfenfluramine, leakiness is the problem. Valvular damage may ultimately produce severe heart and/or lung disease.

7. What is the relationship of fenfluramine and dexfenfluramine to heart disease?

Patients who have taken those drugs may have changes in their heart valves that cause leakiness and backflow of blood. If this is severe, the heart has to work harder. This may cause problems in heart function. However, the full medical implications of this relationship, especially in the asymptomatic patients, is not fully understood.

8. What are the signs and symptoms of valvular heart disease?

The patient may have no symptoms. The physician may hear a new heart murmur (abnormal sound as the blood flows over a valve), or the changes may be detected with a painless, non-invasive special heart test called an echocardiogram. An echocardiogram is usually performed by a cardiologist. If the disease is severe, the patient may experience such symptoms as shortness of breath, excessive tiredness, chest pain, fainting, and swelling of the legs (edema).

9. Is the valve disease reversible?

It is not known at this time. One report has been submitted to FDA in which the valve disease appeared to improve. However, we encourage those people who have taken fenfluramine or dexfenfluramine to contact their physician and discuss the appropriate follow-up, even after stopping their medicine. The full medical implications of these findings are not known at this time, especially as they relate to the asymptomatic valvular changes. The FDA and other government agencies, the manufacturers, and medical researchers will aggressively follow this concern and keep patients and health care providers informed of what is learned about the natural history of the valvular disease caused by these medications.

10. How is valvular disease treated?

It depends on the degree of damage. Medications may help the heart function. If the damage is severe, the valves may have to be replaced surgically.

11. Should I stop taking fen-phen, fenfluramine or dexfenfluramine right now?

Yes, this is the FDA's recommendation. Although we believe these drugs can be stopped at once for most persons, you should consult your physician about whether he/she advises you to taper the dosage over, for example, a 1 to 2 week period. The manufacturers of these drugs are withdrawing fenfluramine and dexfenfluramine from the marketplace, effective September 15, as the concerns about the effects of these drugs on heart valves continue to grow. The drugs will no longer be available in pharmacies. Though the potential long-term medical implications are not known at this time as there are still a number of unanswered questions, the FDA and the manufacturers believe it is in the best interest of the patients that they stop taking these medications. Please be aware that at present this recommendation does not apply to phentermine taken alone.

12. Should I get an echocardiogram if I've been taking fenfluramine or dexfenfluramine?

You should consult your physician about having an echocardiogram. Your physician's recommendation will depend upon your symptoms, if any, his or her examination of you and your history of exposure to these drugs.

13. Does "herbal fen-phen" have the same problem?

Herbal fen-phen is a product that does not contain fenfluramine, dexfenfluramine, or phentermine. Products called "herbal fen-phen" often contain a combination of ephedra (an ephedrine containing herb) and caffeine, but may also contain other herbal ingredients. FDA has not reviewed these herbal products for safety or efficacy. Ephedrine is pharmacologically different from fenfluramine and dexfenfluramine.

14. Can selective serotonin reuptake inhibitor (SSRI) antidepressants such as Prozac, Zoloft, Luvox and Paxil be substituted for fenfluramine in the phen/fen combination?

FDA has not reviewed the safety or efficacy of such combinations and has not approved their use. These drugs are active in serotonin metabolism but have somewhat different activity than fenfluramine and dexfenfluramine. No currently available weight-loss drugs have been studied adequately in combinations to permit a recommendation by FDA for combined use.

15. I have heard the FDA recently denied a citizen petition that sought to suspend the approval of Redux (dexfenfluramine). Why did the FDA deny that request?

The citizen petition did not contain any additional medical information that was not already known. The FDA had taken appropriate actions based on the knowledge at that time. Since that time, more information has been obtained that raised enough additional concerns to warrant withdrawal of Redux from the market.

16. Is this just a disease of women?

Though the majority of cases of which FDA is aware are women, there is no reason at present to believe that men are not also at risk. Most of the use of these products is in women, so what we have seen to date could be only a reflection of the usage patterns of the products. FDA advises that both male and female patients consult their health care professionals.